Test may miss diabetes in some African-Americans

More than 200 scientists from around the world teamed up to study the genetics of hemoglobin A1c (HbA1c), or "glycated hemoglobin", a measurement used by clinicians to diagnose and monitor diabetes. The authors report that they have identified 60 genetic variants that influence HbA1c measurements, as well as the ability of this test to diagnose diabetes. The gene variants, including one that could lead to African Americans being underdiagnosed with T2D, are described in PLOS Medicine in a paper by James Meigs of Harvard Medical School, USA, and Inês Barroso of the Wellcome Trust Sanger Institute, UK, and colleagues.

Levels of HbA1c in a given person depend on both blood glucose levels and characteristics of that person's red blood cells. In the new work, researchers analyzed genetic variants associated with each of these factors, together with HbA1c levels in 160,000 people without diabetes from European, African, and Asian ancestry who had participated in 82 separate studies worldwide. 33,000 people were followed over time to determine whether they were later diagnosed with diabetes.

The team identified 60 genetic variants--42 new and 18 previously known--that impact a person's HbA1c levels. People who had more variants that affect HbA1c levels through effects on blood glucose levels were more likely, over time, to develop diabetes (odds ratio 1.05 per HbA1c-raising allele, P=3x10-29). However, people who had more variants that affected HbA1c through effects on red blood cells did not have an increased diabetes risk. The impact of genetic variants on HbA1c levels was largest in those of African ancestry, and the difference could be explained by variation in the gene G6PD (encoding an enzyme related to red blood cell lifespan) which was associated with lower HbA1c levels. 11% of people of African American ancestry carry at least one copy of this genetic variation, which can lower levels of HbA1c despite high blood glucose levels.

"HbA1c remains an appropriate diagnostic test for the majority of people of diverse genetic backgrounds," the authors say. "Nevertheless, non-glycemic lowering of measured HbA1c for one in ten African American men who carry this G6PD variant, and one in a hundred African American women homozygous for this variant, could amount to 0.65 million African American adults in the United States with a missed T2D diagnosis using HbA1c as a screening test. We therefore recommend investigation of the possible benefits of screening for the G6PD genotype along with HbA1c."

In an accompanying Perspective, Andrew Paterson of the University of Toronto, Canada notes that the impact of the G6PD gene variant on HbA1c results could contribute to the higher risk for long-term diabetes complications in African Americans compared to Americans of European ancestry. "National clinical practice need to be revisited," he writes. "Individuals with this variant should either be screened for T2D using glucose, or sex-and genotype-adjusted thresholds for HbA1c should be used."

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Research Article

Funding:

Please refer to the supporting information file S1 Financial Disclosure for full information with regard to funding and financial support. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Competing Interests:

I have read the journal's policy and the authors of this manuscript have the following competing interests: AYC is an employee of Merck, however all work for the manuscript was completed before the start of employment. CEE is a current employee of AstraZeneca. CLan receives a stipend as a specialty consulting editor for PLOS Medicine and serves on the journal's editorial board. EI is a scientific advisor for Precision Wellness, Cellink and Olink Proteomics for work unrelated to the present project. GKH declared institution support from Amgen, AstraZeneca, Cerenis, Ionis, Regeneron Pharmaceuticals, Inc. and Sanofi, Synageva. He has served as a consultant and received speaker fees from Aegerion, Amgen, Sanofi, Regeneron Pharmaceuticals, Inc., and Pfizer. IB and spouse own stock in GlaxoSmithKline and Incyte Corporation. JD declared grants from the National Heart, Lung, and Blood Institute (NHLBI) of the National Institute of Health (NIH) during the course of this study. JIR declared funding from NIH grants. MAN consults for Illumina Inc, the Michael J. Fox Foundation and University of California Healthcare among others. MBl receives speaker's honoraria and/or compensation for participation in advisory boards from: Astra Zeneca, Bayer, Boehringer-Ingelheim, Lilly, Novo Nordisk, Novartis, MSD, Pfizer, Riemser and Sanofi. MIM was a member of the editorial board of PLOS Medicine at the time this manuscript was submitted. RAS is an employee and shareholder in GlaxoSmithKline.

Department of Human Genetics, Wellcome Trust Sanger Institute, Genome Campus, Hinxton, Cambridge, United Kingdom
Division of General Internal Medicine, Massachusetts General Hospital, Boston, Massachusetts,
United States of America
Harvard Medical School, Boston, Massachusetts, United States of America
Department of Biostatistics, Boston University School of Public Health, Boston, Massachusetts, United States of America
Department of Population Medicine, Harvard Medical School, Harvard Pilgrim Health Care Institute, Boston, Massachusetts, United States of America
Massachusetts General Hospital, Boston, Massachusetts, United States of America
Cardiovascular Medicine Unit, Department of Medicine Solna, Karolinska Institutet, Stockholm,
Sweden
Centre for Molecular Medicine, L8:03, Karolinska Universitetsjukhuset, Solna, Sweden
MRC Epidemiology Unit, Institute of Metabolic Science, University of Cambridge School of Clinical Medicine, Cambridge, United Kingdom
Department of Internal Medicine, Lausanne University Hospital (CHUV), Lausanne, Switzerland
Department of Epidemiology, The Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, United States of America
Division of Nephrology, University of Utah, Salt Lake City, UT, United States of America
Department of Human Genetics, University of Utah, Salt Lake City, UT, United States of America
Institute for Translational Genomics and Population Sciences, Department of Pediatrics, LABioMed at Harbor-UCLA Medical Center, Torrance, CA, United States of America
Saw Swee Hock School of Public Health, National University of Singapore, Singapore, Singapore
National Heart, Lung, and Blood Institute's Framingham Heart Study, Framingham, MA, United States of America
Division of Preventive Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, United States of America
Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, Norfolk Place, London, United Kingdom
Department of Cardiology, Ealing Hospital NHS Trust, Uxbridge Road, Southall, Middlesex, United Kingdom
Life Sciences Institute, National University of Singapore, Singapore, Singapore
Phoenix Epidemiology and Clinical Research Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Phoenix, AZ, United States of America
Key Laboratory of Pathobiology, Ministry of Education, Jilin University, Changchun, Jilin, China
College of Basic Medical Sciences, Jilin University, Changchun, Jilin, China
Division of General Internal Medicine, The Johns Hopkins University School of Medicine, Baltimore, MD, United States of America
Welch Center for Prevention, Epidemiology and Clinical Research, The Johns Hopkins University, Baltimore, MD, United States of America
Division of Epidemiology, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, United States of America
Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan
University of Virginia Center for Public Health Genomics, Charlottesville, VA, United States of America
Personalised Healthcare & Biomarkers, Innovative Medicines and Early Development Biotech Unit, AstraZeneca, Cambridge, United Kingdom
California Pacific Medical Center Research Institute, San Francisco, California, United States of America
Centre for Quantitative Medicine, Duke-NUS Medical School, Singapore, Singapore
Division of Structural and Functional Genomics, Center for Genome Science, Korean National Institute of Health, Osong, Chungchungbuk-do, South Korea
Biological Psychology, Vrije Universiteit Amsterdam, Van der Boechorststraat 1, Amsterdam, Netherlands
The Key Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, University of the Chinese Academy of Sciences, Shanghai, People's Republic of China
Department of Biostatistics and Center for Statistical Genetics, University of Michigan, Ann Arbor, United States of America
William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, United Kingdom
Vth Department of Medicine, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany
Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University, Uppsala, Sweden
Lund University Diabetes Centre, Lund University, Lund, Sweden
University of Lille, CNRS, Institut Pasteur of Lille, UMR 8199ÐEGID, Lille, France
Singapore Eye Research Institute, The Academia Level 6, Discovery Tower, Singapore, Singapore
The Charles Bronfman Institute for Personalized Medicine, The Icahn School of Medicine at Mount Sinai, New York, NY, United States of America
The Genetics of Obesity and Related Metabolic Traits Program, The Icahn School of Medicine at Mount Sinai, New York, NY, United States of America
Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, United Kingdom
Institute of Epidemiology II, Research Unit of Molecular Epidemiology, Helmholtz Zentrum MuÈnchen, German Research Center for Environmental Health, Neuherberg, Germany
German Center for Diabetes Research (DZD e.V.), Partner Munich, Munich, Germany
Data Tecnica International, Glen Echo, MD, United States of America
Laboratory of Neurogenetics, National Institute on Aging, Bethesda, MD, United States of America
MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Western General Hospital, Edinburgh, Scotland
Department of Epidemiology, University of Groningen, University Medical Center Groningen, RB, Groningen, The Netherlands
Data Coordinating Center, Boston University School of Public Health, Boston, MA, United States of America
Istituto di Ricerca Genetica e Biomedica (IRGB), CNR, Monserrato, Italy
Department of Preventive Medicine, University of Southern California, Los Angeles, CA, United States of America
Department of Gene Diagnostics and Therapeutics, Research Institute, National Center for Global Health and Medicine, Tokyo, Japan
Department of Endocrinology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands
MRC Unit for Lifelong Health & Ageing, London, United Kingdom
Division of Cardiovascular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford, OX3 9DU, United Kingdom
Spanish Biomedical Research Centre in Diabetes and Associated Metabolic Disorders
(CIBERDEM), Instituto de InvestigacioÂn Sanitaria del Hospital ClõÂnico San Carlos (IdISSC), Madrid, Spain
Institute for Community Medicine, University Medicine Greifswald, Greifswald, Germany
National Institute for Health and Welfare (THL), Helsinki, Finland
University of Helsinki, Institute for Molecular Medicine, Finland (FIMM) and Diabetes and Obesity Research Program, Helsinki, Finland
Translational Gerontology Branch, National Institute on Aging, Baltimore, MD, United States of America
Department of Clinical Epidemiology, Biostatistics and Bioinformatics, Academic Medical Center, University of Amsterdam, Amsterdam, DE, Netherlands
Durrer Center for Cardiogenetic Research, ICIN-Netherlands Heart Institute, Utrecht, DG, Netherlands
Department of Epidemiology and Prevention, Wake Forest School of Medicine, Winston-Salem NC, United States of America
Integrated Research and Treatment (IFB) Center Adiposity Diseases, University of Leipzig, Liebigstrasse Leipzig, Germany
Centre for Global Health Research, Usher Institute of Population Health Sciences and Informatics, University of Edinburgh, Teviot Place, Edinburgh, Scotland
Laboratory of Clinical Investigation, National Institute on Aging, Baltimore, MD, United States of America
School of Chinese Medicine, China Medical University, North Dist., Taichung City, Taiwan
Department of Biomedical Science, Hallym University, Chuncheon, Gangwon-do, South Korea
Department of Nutrition Sciences, University of Alabama at Birmingham and the Birmingham Veterans Affairs Medical Center, Birmingham, AL, United States of America
Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, United States of America
Department of Psychiatry, University of Groningen, University Medical Center Groningen, AB, Groningen, Netherlands
Institute for Clinical Diabetology, German Diabetes Center, Leibniz Institute for Diabetes Research at Heinrich Heine University Dusseldorf, Dusseldorf, Germany
German Center for Diabetes Research (DZD), Munchen-Neuherberg, Germany
Division of Endocrinology, Diabetes, Metabolism, Department of Internal Medicine, Wexner Medical Center, The Ohio State University, Columbus, OH, United States of America
Boston VA Research Institute, Inc., Boston, MA, United States of America
Department of Geriatric Medicine, Ehime University Graduate School of Medicine, Ehime, Japan
Department of Clinical Gene Therapy, Osaka University Graduate School of Medicine, Suita, Japan
Department of Geriatric Medicine and Nephrology, Osaka University Graduate School of Medicine, Suita, Japan
Genome Institute of Singapore, Agency for Science Technology and Research, Singapore, Singapore
Center of Pediatric Research, University Hospital for Children & Adolescents, Dept. of Women's & Child Health, University of Leipzig, Leipzig, Germany
LIFE Child, LIFE Leipzig Research Center for Civilization Diseases, University of Leipzig, Leipzig, Germany
Faculty of Collaborative Regional Innovation, Ehime University, Ehime, Japan
Department of Medical Research, Taichung Veterans General Hospital, Taichung, Taiwan
Institute of Human Genetics, Technische Universitèt Muènchen, Munich, Germany
Institute of Human Genetics, Helmholtz Zentrum MuÈnchen, Neuherberg, Germany
Munich Cluster for Systems Neurology (SyNergy), Munich, Germany
Department of Epidemiology, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America
Center for Evidence-based Healthcare, University Hospital and Medical Faculty Carl Gustav Carus, TU Dresden Fetscherstrasse 74, Dresden, Germany
Institute of Genetic Epidemiology, Helmholtz Zentrum MuènchenÐ German Research Center for Environmental Health, Neuherberg, Germany
Department of Medicine I, University Hospital Grosshadern, Ludwig-Maximilians-Universitèt, Munich, Germany
DZHK (German Centre for Cardiovascular Research), partner site Munich Heart Alliance, Munich, Germany
Laboratory of Genetics, National Institute on Aging, Baltimore, MD, United States of America
Institute for Clinical Chemistry and Laboratory Medicine, University Medicine Greifswald, Greifswald, Germany
Division of Epidemiology and Community Health, University of Minnesota, Minneapolis, MN, United States of America
University of Split, Split, Croatia
Centre for Population Health Sciences, University of Edinburgh, Edinburgh, United Kingdom
Oxford Centre for Diabetes, Endocrinology and Metabolism, Radcliffe Department of Medicine, University of Oxford, Oxford, United Kingdom
Department of Genomics of Common Disease, School of Public Health, Imperial College London, London, United Kingdom
Department of Medicine, Medical University of South Carolina, Charleston, SC, United States of America
Department of Preventive Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, United States of America
Center for Public Health Genomics, University of Virginia School of Medicine, Charlottesville, VA, United States of America
Wellcome Trust Centre for Human Genetics, Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom
Department of Endocrinology and Diabetology, University Hospital Dusseldorf, Dusseldorf, Germany
INSERM, UMR S 1138, Centre de Recherche des Cordelier, 15 rue de l'Ecole de MeÂdecine, Paris, France
Universite Paris Diderot, Sorbonne Paris Cite, UFR de Medecine, 16 rue Henri Huchard, Paris, France
Assistance Publique Hopitaux de Paris, Bichat Hospital, DHU FIRE, Department of Diabetology, Endocrinology and Nutrition, 46 rue Henri Huchard, Paris, France
University of Edinburgh, Edinburgh, United Kingdom
Science for life laboratory, Karolinska Institutet, Tomtebodavagen 23A, Solna, Sweden
The New York Academy of Medicine, New York, City, NY, United States of America
Institute of Medical Informatics, Biometry and Epidemiology, Chair of Genetic Epidemiology, Ludwig-Maximilians-Universitat, Munich, Germany
Department of Genetics, University of Groningen, University Medical Center Groningen, RB, Groningen, Netherlands
Health Disparities Unit, National Institute on Aging, National Institutes of Health, Baltimore, MD, United States of America
Department of Statistics and Applied Probability, National University of Singapore, Singapore,
Singapore
NUS Graduate School for Integrative Science and Engineering, National University of Singapore, Singapore, Singapore
Department of Medicine; University of Leipzig, Liebigstrasse 18, Leipzig, Germany
Dept of Community Medicine, Faculty of Health Sciences, University of Tromsø, Tromsø, Norway
Institute of Cardiovascular Science, University College London, London, United Kingdom
Department of Vascular Medicine, Academic Medical Center, Amsterdam, The Netherlands
Department of Epidemiology and Public Health, University College London, London, United Kingdom
Institute for Social and Economic Research, University of Essex, Colchester, United Kingdom
Pat Macpherson Centre for Pharmacogenetics and Pharmacogenomics, Medical Research Institute, Ninewells Hospital and Medical School, Dundee, United Kingdom
Ophthalmology and Visual Sciences Academic Clinical Program (Eye ACP), Duke-NUS Medical School, Singapore, Singapore
Department of Ophthalmology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
Singapore National Eye Centre, Singapore, Singapore
Dept of Medicine III, University of Dresden, Medical Faculty Carl Gustav Carus, Fetscherstrasse 74, Dresden, Germany
Imperial College Healthcare NHS Trust, London, United Kingdom
Division of Genetics, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, United States of America
Broad Institute of MIT and Harvard, Cambridge, MA, United States of America
Dipartimento di Scienze Biomediche, Università di Sassari, SS, Italy
Princess Al-Jawhara Al-Brahim Centre of Excellence in Research of Hereditary Disorders (PACER-HD), King Abdulaziz University, Jeddah, Saudi Arabia
Brown Foundation Institute of Molecular Medicine, Division of Epidemiology, School of Public Health, University of Texas Health Science Center at Houston, Houston, Texas, United States of America
Braun School of Public Health, Hebrew University-Hadassah Medical Center, Jerusalem, Israel
CNRS 8199-Lille University, France
Finnish Institute for Molecular Medicine (FIMM), Helsinki, Finland
Department of Laboratory Medicine and Pathology, University of Minnesota, 420 Delaware Street Minneapolis, MN, United States of America
National Institute on Aging, Bethesda, Maryland, United States of America
Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, United Kingdom
Department of Paediatrics, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
Khoo Teck Puat-National University Children's Medical Institute, National University Health System, Singapore, Singapore
Department of Medical Sciences, Molecular Epidemiology and Science for Life Laboratory, Uppsala University, Uppsala, Sweden
Department of Medicine, Division of Cardiovascular Medicine, Stanford University School of Medicine, Stanford, CA, United States of America
Duke-NUS Medical School Singapore, Singapore
National Heart and Lung Institute, Imperial College London, Hammersmith Hospital Campus, London, United Kingdom
Institute of Clinical Medicine, Internal Medicine, University of Eastern Finland and Kuopio University Hospital, Kuopio, Finland
Department of Epidemiology and Prevention, Division of Public Health Sciences, Wake Forest University, Winston-Salem, North Carolina, United States of America
The Mindich Child Health Development Institute, The Icahn School of Medicine at Mount Sinai, New York, NY, United States of America
Department of Medical Epidemiology and Biostatistics, Karolinska Insitutet, Novels vag 12a, Stockholm, Sweden
Clinical Institute of Medical and Chemical Laboratory Diagnostics, Medical University of Graz, Graz, 8036, Austria
Synlab Academy, Synlab Services GmbH, Mannheim, Germany
Oxford NIHR Biomedical Research Centre, Oxford University Hospitals Trust, Oxford, United Kingdom
Division of Cardiovascular Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, United States of America
Department of Biostatistics and Epidemiology, University of Pennsylvania, Philadelphia, PA, United States of America
Center for Non-Communicable Diseases, Karachi, Pakistan
Department of Medicine, Central Hospital, Central Finland, Jyvaskyla, Finland
Division of Endocrine and Metabolism, Department of Internal Medicine, Taichung Veterans General Hospital, Taichung, Taiwan
School of Medicine, National Yang-Ming University, Taipei, Taiwan
School of Medicine, National defense Medical Center, Taipei, Taiwan
Department of Twin Research and Genetic Epidemiology, King's College London, London, United Kingdom
Center for Genomic Medicine, Kyoto University Graduate School of Medicine, Kyoto, Japan
Chronic Disease Prevention Unit, National Institute for Health and Welfare, Helsinki, Finland
Dasman Diabetes Institute, Dasman, Kuwait
Centre for Vascular Prevention, Danube-University Krems, Krems, Austria
Saudi Diabetes Research Group, King Abdulaziz University, Fahd Medical Research Center, Jeddah, Saudi Arabia
Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson, MS, United States of America
Division of Cancer Control and Population Sciences, University of Pittsburgh Cancer Institute, Pittsburgh, PA, United States of America
Laboratory of Epidemiology & Population Sciences, National Institute on Aging, National Institutes of Health, Baltimore, MD, United States of America
Department of Haematology, University of Cambridge, Hills Rd, Cambridge, United Kingdom
The National Institute for Health Research Blood and Transplant Unit (NIHR BTRU) in Donor Health and Genomics at the University of Cambridge, United Kingdom
Biomedical Research Centre Oxford Haematology Theme and Radcliffe Department of
Medicine, University of Oxford, John Radcliffe Hospital, Headley Way, Headington, Oxford, United Kingdom
NHS Blood and Transplant, Headington, Oxford, United Kingdom
Diabetes Unit and Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA, United States of America
Programs in Metabolism and Medical & Population Genetics, Broad Institute, Cambridge, MA,
United States of America
Department of Medicine, McGill University, Montreal, Quebec, Canada
Department of Biostatistics, University of Liverpool, Liverpool, United Kingdom
Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
Institute of Metabolic Science, University of Cambridge, Cambridge, United Kingdom

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